This application claims the benefit of foreign priority under 35 U.S.C. xc2xa7119 of German patent application no. 10046993.0, filed on Sep. 22, 2000, the contents of which are incorporated by reference herein.
The invention relates to substituted cinnamic acid guanidides of the formula I 
in which:
at least one of R(1), R(2), R(3), R(4) and R(5) is xe2x80x94Xaxe2x80x94Ybxe2x80x94Lnxe2x80x94U;
X is CR(16)R(17), O, S or NR(18);
where R(16), R(17) and R(18) independently of one another are H or an alkyl having 1, 2, 3 or 4 carbon atoms, where the alkyl is chosen from unsubstituted alkyls, partially fluorinated alkyls and completely fluorinated alkyls;
a is zero or;
Y is alkylene having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkylene-T having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in the alkylene group, T, or T-alkylene having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in the alkylene group;
where T is NR(20), phenylene, O or S, where the phenylene is not substituted or is substituted by 1-3 substituents chosen from F, Cl, CF3, methyl, methoxy and NR(21)R(22);
where R(20), R(21) and R(22) independently of one another are H or an alkyl having 1, 2, 3 or 4 carbon atoms, where the alkyl is chosen from unsubstituted alkyls, partially fluorinated alkyls and completely fluorinated alkyls;
b is zero or 1;
L is O, S, NR(23) or CkH2k;
where k is 1, 2, 3, 4, 5, 6, 7 or 8;
where R(23) is H or an alkyl group having 1, 2, 3 or 4 carbon atoms, where the alkyl is chosen from unsubstituted alkyls, partially fluorinated alkyls and completely fluorinated alkyls;
n is zero or 1;
U is 
xe2x80x83or a nitrogen-containing heterocycle having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, which is substituted by an xe2x80x94SO2NR(30)R(31)-group;
where R(30) and R(31) independently of one another are H or an alkyl group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
where in the alkyl group, independently of one another, one or more CH2 groups can be replaced by O, NR(35), Cxe2x95x90O, S or Cxe2x95x90S;
where R(35) is H or alkyl having 1, 2, 3 or 4 carbon atoms, where the alkyl is chosen from unsubstituted alkyls, partially fluorinated alkyls and completely fluorinated alkyls; or
R(30) and R(31) independently of one another are H, an alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, where the alkyl is chosen from partially fluorinated alkyls and completely fluorinated alkyls, (C3-C8)-cycloalkyl, phenyl-(C1-C4)-alkyl or (C3-C8)-cycloalkyl-(C1-C4)-alkyl,
where in the alkyl or in the cycloalkyl ring, independently of one another, one or more CH2 groups can be replaced by 0, NR(35), Cxe2x95x90O, S or Cxe2x95x90S; or
R(30) and R(31) together are 4 or 5 methylene groups,
where, independently of one another, one or more CH2 groups can be replaced by O, NR(35), Cxe2x95x90O, S or Cxe2x95x90S; or
R(31) and R(35) together are 4 or 5 methylene groups;
R(32), R(33) and R(34) independently of one another are H, F, Cl, Br, I, (C1-C4)-alkyl, partially fluorinated (C1-C4)-alkyl, completely fluorinated (C1-C4)-alkyl, Oxe2x80x94(C1-C4)-alkyl, partially fluorinated Oxe2x80x94(C1-C4)-alkyl, completely fluorinated Oxe2x80x94(C1-C4)-alkyl, NO2, or NR(28)R(29);
where R(28) and R(29) independently of one another are H or an alkyl having 1, 2, 3 or 4 carbon atoms, where the alkyl is chosen from unsubstituted alkyls, partially fluorinated alkyls and completely fluorinated alkyls;
where the N-containing heterocycles are N- or C-bridged and are unsubstituted or are substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(36)R(37);
R(36) and R(37) independently of one another are H, an alkyl having 1, 2, 3 or 4 carbon atoms, where the alkyl is chosen from unsubstituted alkyls, partially fluorinated, and completely fluorinated alkyls, or benzyl;
and the remaining substituents of R(1), R(2), R(3), R(4) and R(5) independently of one another are H, F, Cl, Br, I, SO2NH2, SO2CH3, NO2, NR(24)R(25), CN, unsubstituted (C1-C8)-alkyl, partially fluorinated (C1-C8)-alkyl, completely fluorinated (C1-C8)-alkyl, unsubstituted Oxe2x80x94(C1-C8)-alkyl, partially fluorinated Oxe2x80x94(C1-C8)-alkyl, completely fluorinated Oxe2x80x94(C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C4)-alkyl or phenyl-(C1-C4)-alkyl,
where the phenyl is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(11)R(12);
R(11), R(12), R(24) and R(25) independently of one another are H or an alkyl having 1, 2, 3 or 4 carbon atoms, where the alkyl is chosen from unsubstituted alkyls, partially fluorinated alkyls and completely fluorinated alkyls;
R(6) and R(7) independently of one another are H, F, Cl, Br, I, CN, an alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, where the alkyl is chosen from unsubstituted alkyls, partially fluorinated alkyls, and completely fluorinated alkyls, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl,
where the phenyl is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(14)R(15);
R(14) and R(15) independently of one another are H or an alkyl having 1, 2, 3 or 4 carbon atoms, where the alkyl is chosen from unsubstituted alkyls, partially fluorinated alkyls and completely fluorinated alkyls;
and their pharmaceutically tolerable salts.
In one embodiment, the compounds of the formula I are those in which:
at least one of the substituents R(1), R(2), R(3), R(4) and R(5) is xe2x80x94Xxe2x80x94U;
X is CR(16)R(17), O, S or NR(18);
R(16), R(17) and R(18) independently of one another are H or an alkyl having 1, 2, 3 or 4 carbon atoms, where the alkyl is chosen from unsubstituted alkyls, partially fluorinated alkyls and completely fluorinated alkyls;
U is 
xe2x80x83or a nitrogen-containing heterocycle having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, which is substituted by an xe2x80x94SO2NR(30)R(31)-group;
R(30) and R(31) independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
where in the alkyl chain, independently of one another, one or more CH2 groups can be replaced by O, NR(35), Cxe2x95x90O, S or Cxe2x95x90S;
R(35) is H or an alkyl having 1, 2, 3, 4 or 5 carbon atoms, where the alkyl is chosen from unsubstituted alkyls, partially fluorinated alkyls and completely fluorinated alkyls; or
R(30) and R(31) independently of one another are H, an alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, where the alkyl is chosen from partially fluorinated alkyl and completely fluorinated alkyl, (C3-C8)-cycloalkyl, phenyl-(C1-C4)-alkyl or (C3-C8)-cycloalkyl-(C1-C4)-alkyl,
where in the alkyl or in the cycloalkyl ring, independently of one another, one or more CH2 groups can be replaced by O, NR(35), Cxe2x95x90O, S or Cxe2x95x90S; or
R(30) and R(31) together are 4 or 5 methylene groups,
where, independently of one another, one or more CH2 groups can be replaced by O, NR(35), Cxe2x95x90O, S or Cxe2x95x90S; or
R(31) and R(35) together are 4 or 5 methylene groups;
R(32), R(33) and R(34) independently of one another are H, F, Cl, Br, I, (C1-C4)-alkyl, Oxe2x80x94(C1-C4)-alkyl, CF3 or NR(28)R(29);
R(28) and R(29) independently of one another are H or alkyl having 1, 2, 3 or 4 carbon atoms;
where the N-containing heterocycles are N- or C-bridged and are not substituted or are substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(36)R(37);
R(36) and R(37) independently of one another are H, an alkyl having 1, 2, 3 or 4 carbon atoms, where the alkyl is chosen from unsubstituted alkyls, partially fluorinated, and completely fluorinated alkyls, or benzyl;
and the remaining substituents of R(1), R(2), R(3), R(4) and R(5) independently of one another are H, F, Cl, Br, I, SO2NH2, SO2CH3, NO2, NR(24)R(25), CN, unsubstituted (C1-C4)-alkyl, partially fluorinated (C1-C4)-alkyl, completely fluorinated (C1-C4)-alkyl, unsubstituted Oxe2x80x94(C1-C4)-alkyl, partially fluorinated Oxe2x80x94(C1-C4)-alkyl, completely fluorinated Oxe2x80x94(C1-C4)-alkyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C4)-alkyl or phenyl-(C1-C4)-alkyl,
where the phenyl is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(11)R(12);
R(11), R(12), R(24) and R(25) independently of one another are H or an alkyl having 1, 2, 3 or 4 carbon atoms, where the alkyl is chosen from unsubstituted alkyls, partially fluorinated alkyls, and completely fluorinated alkyls;
R(6) and R(7) independently of one another are hydrogen, F, Cl, Br, I, CN, an alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, where the alkyl is chosen from unsubstituted alkyls, partially fluorinated alkyls, and completely fluorinated alkyls, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl,
which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(1 4)R(1 5);
R(14) and R(15) independently of one another are H, alkyl having 1, 2, 3 or 4 carbon atoms, where the alkyls are chosen from unsubstituted alkyls, partially fluorinated alkyls and completely fluorinated alkyls;
and their pharmaceutically tolerable salts.
In another embodiment, the compounds of the formula I are those in which:
at least one of the substituents R(1), R(2), R(3), R(4) and R(5) is xe2x80x94Xxe2x80x94U;
X is CR(16)R(17), O, S or NR(18);
R(16), R(17) and R(18) independently of one another are H, alkyl having 1, 2, 3 or 4 carbon atoms or CF3;
U is 
xe2x80x83or a nitrogen-containing heterocycle having 1, 2, 3, 4, 5 or 6 carbon atoms, which is substituted by an xe2x80x94SO2NR(30)R(31) group;
R(30) and R(31) independently of one another are H, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, CF3, (C3-C8)-cycloalkyl, where in the alkyl, independently of one another, one or more CH2 groups can be replaced by O, NR(35), Cxe2x95x90O, S or Cxe2x95x90S;
where R(35) is H or alkyl having 1, 2, 3, 4 or 5 carbon atoms; or
R(30) and R(31) together are 4 or 5 methylene groups,
where, independently of one another, one or more CH2 groups can be replaced by O, NR(35), Cxe2x95x90O, S or Cxe2x95x90S; or
R(31) and R(35) together are 4 or 5 methylene groups;
R(32), R(33) and R(34) independently of one another are H, F, Cl, methyl, ethyl, Omethyl, Oethyl, CF3, NH2, NHmethyl or Nmethyl2;
where the N-containing heterocycles are N- or C-bridged and are not substituted or are substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(36)R(37);
R(36) and R(37) independently of one another are H, alkyl having 1, 2, 3 or 4 carbon atoms, CF3 or benzyl;
and the remaining substituents of R(1), R(2), R(3), R(4) and R(5) independently of one another are H, F, Cl, Br, I, SO2NH2, SO2CH3, NR(24)R(25), CN, (C1-C4)-alkyl, CF3, C2F5, Oxe2x80x94(C1-C4)-alkyl, OCF3, OC2F5, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C4)-alkyl or phenyl-(C1-C4)-alkyl,
where the phenyl is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(11)R(12);
R(11), R(12), R(24) and R(25) independently of one another are H or alkyl having 1, 2, 3 or 4 carbon atoms;
R(6) and R(7) independently of one another are hydrogen, F, Cl, Br, I, CN, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, CF3, cycloalkyl having 3, 4, 5 or 6 carbon atoms;
and their pharmaceutically tolerable salts.
In a further embodiment, compounds of the formula I are those in which:
at least one of the substituents R(1), R(2), R(3), R(4) and R(5) is xe2x80x94Xxe2x80x94U;
X is CR(16)R(17), O, S or NR(18);
R(16), R(17) and R(18) independently of one another are H, CH3, C2H5 or CF3;
U is 
xe2x80x83or an N-containing heterocycle having 3, 4 or 5 carbon atoms, which is substituted by an xe2x80x94SO2NR(30)R(31)-group;
R(30) and R(31) independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, CF3, (C3-C8)-cycloalkyl;
where in the alkyl, independently of one another, one or more CH2 groups can be replaced by O, NR(35), Cxe2x95x90O, S or Cxe2x95x90S;
R(35) is H or alkyl having 1, 2, 3, 4 or 5 carbon atoms; or
R(30) and R(31) together are 4 or 5 methylene groups,
where, independently of one another, one or more CH2 groups can be replaced by O, NR(35), Cxe2x95x90O, S or Cxe2x95x90S; or
R(31) and R(35) together are 4 or 5 methylene groups;
R(32), R(33) and R(34) independently of one another are H, F, Cl, methyl, CF3;
where the N-containing heterocycles are N- or C-bridged and are not substituted or are substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(36)R(37);
R(36) and R(37) independently of one another are H, CH3, C2H5 or CF3;
and the remaining substituents of R(1), R(2), R(3), R(4) and R(5) independently of one another are H, F, Cl, SO2NH2, SO2CH3, NR(24)R(25), CN, (C1-C4)-alkyl, CF3, C2F5, Oxe2x80x94(C1-C4)-alkyl, OCF3, OC2F5, (C3-C6)-cycloalkyl or (C3-C6)-cycloalkyl-(C1-C4)-alkyl;
R(24) and R(25) independently of one another are H, alkyl having 1, 2, 3 or 4 carbon atoms;
R(6) and R(7) independently of one another are H, F, Cl, Br, I, CN, CH3 , C2H5, CF3 or cycloalkyl having 3, 4, 5 or 6 carbon atoms;
and their pharmaceutically tolerable salts.
If the compounds of the formula I contain one or more centers of asymmetry, these can have either the S or R configuration. The compounds may be present as optical isomers, as diastereomers, as racemates or as mixtures thereof, including mixtures of at least one stereoisomeric form and at least one pharmaceutically tolerable salt.
The double bond geometry of the compounds of the formula I may be either E or Z. The compounds may be present in a mixture of double bond isomers.
The designated alkyls, including substituted alkyls partially fluorinated alkyls and completely fluorinated alkyls may be chosen from straight-chain alkyls or branched alkyls.
N-containing heterocycles having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms include, but at not limited to, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl.
In one embodiment, the N-containing heterocycles are chosen from pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.
In a further embodiment, the N-containing heterocycles is chosen from Pyridyl.
The invention furthermore relates to a process for the preparation of the compounds I, which comprises reacting a compound of the formula II 
in which R(1) to R(7) have the meanings indicated and L is an easily nucleophilically substitutable leaving group, with guanidine.
Examples of leaving groups include, but are not limited to,: xe2x80x94OMe, xe2x80x94OEt, xe2x80x94OPh, xe2x80x94SPh, xe2x80x94SMe, and 1-imidazolyl.
The activated acid derivatives of the formula 11, in which L is an alkoxy group, for example a methoxy group, a phenoxy group, phenylthio group, methylthio group or 2-pyridylthio group, a nitrogen heterocycle, for example 1-imidazolyl, may be obtained, for example, in a manner known per se from the carboxylic acid chlorides on which they are based (formula II, L=Cl), which for their part may in turn be prepared in a manner known per se from the carboxylic acids on which they are based (formula II, L=OH), for example using thionyl chloride.
Beside the carboxylic acid chlorides of the formula II (L=Cl), other activated acid derivatives of the formula II may also be prepared directly from the benzoic acid derivatives on which they are based (formula II, L=OH) in a manner known per se, such as the methyl esters of the formula II with L=OCH3 by treating with gaseous HCl in methanol, the imidazolides of the formula II by treating with carbonyldiimidazole [L=1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)], the mixed anhydrides II with Clxe2x80x94COOC2H5 or tosyl chloride in the presence of triethylamine in an inert solvent, and the activation of benzoic acids with dicyclohexylcarbodiimide (DCC) or with O-[(cyano(ethoxycarbonyl)methylene)-amino]-1,1,3,3-tetramethyluroniumtetrafluoroborate (xe2x80x9cTOTUxe2x80x9d) [Proceedings of the 21st European Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991]. A number of suitable methods for the preparation of activated carboxylic acid derivatives of the formula II are given with details of the source literature in J. March, Advanced Organic Chemistry, Third Edition (John Wiley and Sons, 1985), p. 350.
The reaction of an activated carboxylic acid derivative of the formula II with guanidine may be carried out in a manner known per se in a protic or aprotic polar but inert organic solvent. In the reaction with guanidine of the methyl or ethyl benzoates (II, L=Ome, OEt), methanol, isopropanol, DMF or THF from 20xc2x0 C. up to the boiling temperature of these solvents may be suitable. Most reactions of compounds II with salt-free guanidine may be carried out in aprotic inert solvents such as THF, DMF, dimethoxyethane or dioxane. IN one embodiment, when using a base such as, for example, NaOH, water may also be used as solvent in the reaction of II with guanidine.
When L=Cl, the reaction may be carried out, for example, with addition of an acid scavenger, e.g. in the form of excess guanidine, for the binding of the hydrohalic acid.
Some of the underlying benzoic acid derivatives of the formula II are known and described in the literature. The unknown compounds of the formula II may be prepared by methods known from the literature. The alkenylcarboxylic acids obtained may be reacted by one of the process variants described above to give compounds I according to the invention.
The introduction of some substituents may be achieved by methods known from the literature of palladium-mediated cross-coupling of aryl halides or aryl triflates with, for example, organostannanes, organoboronic acids or organoboranes or organocopper or -zinc compounds.
In general, carboxylguanidines I are weak bases and may bind acid with formation of salts. Possible acid addition salts include, but are not limited to, salts of all pharmacologically tolerable acids, for example halides, such as hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates and p-toluenesulfonates.
The compounds I may be substituted acylguanidines.
Similar cinnamic acid guanidides are disclosed in European laid-open publication 755 919 (HOE 94/F 168), but these known compounds do not meet all desired requirements. Using the compounds of the formula I, it was possible to achieve improved water solubility, which may result in increased excretion via the kidneys. Moreover, in one embodiment, the compounds of the formula I show a very good inhibitory action on NHE3 (Na+/H+ exchanger subtype 3). This may be achieved by the compounds according to the invention, which, in one embodiment, have no undesired and disadvantageous salidiuretic properties, but very good antiarrhythmic properties, such as are useful, for example, for the treatment of illnesses which are caused by oxygen deficiency. As a result of their pharmacological properties, the compounds may be suitable, as antiarrhythmic pharmaceuticals having a cardioprotective component, for infarct prophylaxis and infarct treatment and also for the treatment of angina pectoris, where they also preventively inhibit or greatly decrease the pathophysiological processes in the formation of ischemically induced damage, in particular in the induction of ischemically induced cardiac arrhythmias.
In one embodiment, because of their protective actions against pathological hypoxic and ischemic situations, the compounds of the formula I according to the invention may be used, as a result of inhibition of the cellular Na+/H+ exchange mechanism, as pharmaceuticals for the treatment of all acute or chronic damage induced by ischemia or illnesses primarily or secondarily induced thereby. This relates to their use as pharmaceuticals for surgical interventions, e.g. in organ transplantation, where the compounds may be used both for the protection of the organs in the donor before and during removal, for the protection of removed organs, for example during treatment with or storage thereof in physiological bath fluids, and during transfer to the recipient""s body. The compounds may also be valuable pharmaceuticals which have a protective action when carrying out angioplastic surgical interventions, for example on the heart and on peripheral vessels. Corresponding to their protective action against ischemically induced damage, the compounds may also be suitable as pharmaceuticals for the treatment of ischemias of the nervous system, in particular of the CNS, where they may be suitable, for example, for the treatment of stroke or of cerebral edema. Moreover, the compounds of the formula I according to the invention may likewise be suitable for the treatment of forms of shock, such as, for example, of allergic, cardiogenic, hypovolemic and of bacterial shock.
In another embodiment, the compounds may furthermore induce an improvement in the respiratory drive and may therefore be used for the treatment of respiratory conditions in the following clinical conditions and illnesses: impaired central respiratory drive (e.g. central sleep apneas, sudden infant death, postoperative hypoxia), muscle-related respiratory disorders, respiratory disorders after long-term respiration, respiratory disorders during adaptation in a high mountain region, obstructive and mixed forms of sleep apneas, acute and chronic lung diseases with hypoxia and hypercapnia.
The compounds may additionally increase the muscle tone of the upper airways, so that snoring is suppressed.
In one embodiment, a combination of an NHE inhibitor with a carboanhydrase inhibitor (e.g. acetazolamide), the latter producing a metabolic acidosis and thereby even increasing the respiratory activity, proves to be a favorable combination with increased action and decreased use of active compound.
It has been shown that the compounds according to the invention may have a mild laxative effect and accordingly may be used as laxatives or if there is a threat of intestinal blockage, the prevention of the ischemic damage which accompanies blockages in the intestinal area being particularly advantageous.
There is furthermore the possibility of preventing gallstone formation.
In another embodiment, the compounds of the formula I according to the invention may moreover be distinguished by strong inhibitory action of the proliferation of cells, for example, fibroblast cell proliferation and the proliferation of vascular smooth muscle cells. The compounds of the formula I may therefore, in one embodiment, be suitable as valuable therapeutics for illnesses in which cell proliferation is a primary or secondary cause, and may therefore be used as antiatherosclerotics, agents against diabetic late complications, carcinomatous disorders, fibrotic disorders such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, organ hypertrophies and hyperplasias, in particular in prostate hyperplasia or prostate hypertrophy.
In a further embodiment, the compounds according to the invention may be effective inhibitors of the cellular sodium-proton antiporter (Na+/H+ exchanger), which is raised in numerous disorders (essential hypertension, atherosclerosis, diabetes etc.) even in those cells which are easily accessible to measurements, such as, for example, in erythrocytes, platelets or leukocytes. The compounds according to the invention may therefore, in one embodiment, be suitable as outstanding and simple scientific tools, for example in their use as diagnostics for the determination and differentiation of certain forms of hypertension, but also of atherosclerosis, of diabetes, proliferative disorders, etc. Moreover, the compounds of the formula I may be suitable for preventive therapy for averting the genesis of high blood pressure, for example of essential hypertension.
It has additionally been found that NHE inhibitors may have a favorable influence on the serum lipoproteins. It is generally recognized that for the formation of arteriosclerotic vascular changes, in particular of coronary heart disease, excessively high blood lipid values, so-called hyperlipoproteinemias, are a significant risk factor. The lowering of raised serum lipoproteins is therefore of extreme importance for the prophylaxis and the regression of atherosclerotic changes. In one embodiment, the compounds according to the invention may therefore be used for the prophylaxis and for the regression of atherosclerotic changes, in that they exclude a causal risk factor. With this protection of the vessels against the endothelial dysfunction syndrome, compounds of the formula I may be valuable pharmaceuticals for the prevention and for the treatment of coronary vasospasms, atherogenesis and atherosclerosis, left-ventricular hypertrophy and dilated cardiomyopathy, and thrombotic disorders.
The compounds mentioned may therefore be used advantageously for the production of a medicament for the prevention and treatment of sleep apneas and muscle-related respiratory disorders; for the production of a medicament for the prevention and treatment of snoring; for the production of a medicament for lowering blood pressure; for the production of a medicament having a laxative effect for the prevention and treatment of intestinal blockages; for the production of a medicament for the prevention and treatment of disorders induced by ischemia and reperfusion of central and peripheral organs, such as acute kidney failure, stroke, endogenous states of shock, intestinal disease etc.; for the production of a medicament for the treatment of hypercholesterolemia; for the production of a medicament for the prevention of atherogenesis and atherosclerosis; for the production of a medicament for the prevention and treatment of diseases which are caused by increased cholesterol levels; for the production of a medicament for the prevention and treatment of diseases which are caused by endothelial dysfunction; for the production of a medicament for the treatment of attack by ectoparasites; for the production of a medicament for the treatment of the illnesses mentioned in combinations with hypotensive substances, preferably with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists. A combination of an NHE inhibitor of the formula I with a blood lipid level-lowering active compound, preferably with an HMG-CoA-reductase inhibitor (e.g. lovastatin or pravastatin), where the latter produces a hypolipidemic action and thereby increases the hypolipidemic properties of the NHE inhibitor of the formula I, proves to be a favorable combination with increased action and decreased use of active compound.
In a further embodiment, the administration of sodium/proton exchange inhibitors of the formula I may be used as novel pharmaceuticals for lowering increased blood lipid levels, and also the combination of sodium/proton exchange inhibitors with hypotensive and/or hypolipidemic pharmaceuticals.
Pharmaceuticals which contain a compound I may in this case be administered, for example, orally, parenterally, intravenously, rectally or by inhalation. In one embodiment, administration is dependent on the particular clinical picture of the disorder. The compounds I may in this case be used on their own or together with pharmaceutical auxiliaries, to be specific both in veterinary and in human medicine.
The person skilled in the art is familiar on the basis of his expert knowledge with auxiliaries which are suitable for the desired pharmaceutical formulation. Beside solvents, gel-forming agents, suppository bases, tablet auxiliaries and other active compound excipients, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers or colorants.
For an oral administration form, the active compounds may, for example, be mixed with the additives suitable for this, such as excipients, stabilizers or inert diluents, and are brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard gelatin capsules, or aqueous, alcoholic or oily solutions. Inert excipients which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. In this case preparation can take place either as dry or as moist granules. Suitable oily excipients or solvents are, for example, vegetable or animal oils, such as sunflower oil or cod liver oil.
For subcutaneous or intravenous administration, the active compounds may be brought into solution, suspension or emulsion, if desired using the substances customary for this, such as solubilizers, emulsifiers or other auxiliaries. Possible solvents are, for example: water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, in addition also sugar solutions such as glucose or mannitol solutions, or alternatively a mixture of the various solvents mentioned.
Suitable pharmaceutical formulations for administration in the form of aerosols or sprays may be, for example, solutions, suspensions or emulsions of the active compound of the formula I in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water, or a mixture of such solvents.
If desired, the formulation may also contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers, as well as a propellant. Such a preparation contains the active compound customarily in a concentration of approximately 0.1 to 10, in particular from approximately 0.3 to 3,% by weight.
The dose of the active compound of the formula I to be administered and the frequency of administrationdepend on the potency and duration of action of the compounds used; additionally also on the nature and severity of the illness to be treated and on the sex, age, weight and individual responsiveness of the mammal to be treated.
On average, the daily dose of a compound of the formula I in the case of a patient approximately 75 kg in weight is at least 0.001 mg/kg, preferably 0.01 mg/kg, to at most 10 mg/kg, preferably 1 mg/kg, of body weight. In acute episodes of the illness, for example, directly after suffering a cardiac infarct, even higher and especially more frequent doses may also be necessary, e.g. up to 4 individual doses per day. In particular on i.v. administration, for example in the case of an infarct patient in. the intensive care unit, up to 200 mg per day may be necessary.
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